Methods, devices and systems for treating insomnia by inducing frontal cerebral hypothermia

ABSTRACT

Method, systems and devices for treating insomnia by non-invasive hypothermic treatment are described. In general, these devices, systems and method enable cooling of the frontal cortex prior to and/or during sleep to enhance sleep, which may be particularly beneficial to treat insomnia.

CROSS REFERENCE TO RELATED APPLICATIONS

This patent application is a continuation of U.S. patent applicationSer. No. 13/019,477, filed Feb. 2, 2011, entitled “METHODS, DEVICES ANDSYSTEMS FOR TREATING INSOMNIA BY INDUCING FRONTAL CEREBRAL HYPOTHERMIA,”now U.S. Pat. No. 8,425,583, which claims priority to U.S. ProvisionalPatent Application No. 61/300,768, filed on Feb. 2, 2010, each of whichis herein incorporated by reference in its entirety.

U.S. patent application Ser. No. 13/019,477 also claims priority as acontinuation-in-part of U.S. patent application Ser. No. 11/788,694,filed Apr. 20, 2007, titled “METHOD AND APPARATUS OF NONINVASIVE,REGIONAL BRAIN THERMAL STIMULATION FOR THE TREATMENT OF NEUROLOGICALDISORDERS,” now U.S. Pat. No. 8,236,038, which claims priority to U.S.Provisional Patent Application No. 60/793,680, filed on Apr. 20, 2006,each of which is herein incorporated by reference in its entirety.

U.S. patent application Ser. No. 13/019,477 also claims priority as acontinuation-in-part of U.S. patent application Ser. No. 12/288,417,filed Oct. 20, 2008, titled “METHOD AND APPARATUS OF NONINVASIVE,REGIONAL BRAIN THERMAL STIMULATION FOR THE TREATMENT OF NEUROLOGICALDISORDERS,” Publication No. US-2009-0054958-A1, each of which is hereinincorporated by reference in its entirety.

INCORPORATION BY REFERENCE

All publications and patent applications mentioned in this specificationare herein incorporated by reference in their entirety to the sameextent as if each individual publication or patent application wasspecifically and individually indicated to be incorporated by reference.

FIELD

Described herein are methods, devices and systems for the treatment ofinsomnia. In particular, described herein are methods, devices andsystems for treatment of insomnia by cooling the frontal (e.g.prefrontal) cortex.

BACKGROUND

Insomnia is most often described as the inability to fall asleep easily,to stay asleep or to have quality sleep in an individual with adequatesleep opportunity. In the U.S., population-based estimates of eitherchronic or transient insomnia range from 10 to 40% of the population, or30 to 120 million adults in the United States. Similar prevalenceestimates have been reported in Europe and Asia. Across studies, thereare two age peaks: 45-64 years of age and 85 years and older. Women are1.3 to 2 times more likely to report trouble sleeping than men, as arethose who are divorced or widowed, and have less education. In the U.S.,the economic burden of insomnia approaches $100 billion, in directhealth care costs, functional impairment, increased risk of mentalhealth problems, lost productivity, worker absenteeism and excess healthcare utilization. It is recognized as a public health problem,contributing to more than twice the number of medical errors attributedto health care workers without insomnia episodes. Currently availabletreatments for insomnia, however, are not entirely satisfactory for avariety of reasons. Sedative-hypnotics are not a complete solution tothe problem of insomnia as they are associated with significant adverseevents such as the potential for addiction/dependence, memory loss,confusional arousals, sleep walking and problems with coordination thatcan lead to falls and hip fractures. The majority of insomnia patientswould prefer a non-pharmaceutical approach to their insomnia complaints.Cognitive behavior therapy, while effective, is an expensive and laborintensive treatment that is not widely available and is not alwayscovered by health insurance. Over-the-counter approaches to thetreatment of insomnia including a variety of medications and devicessuffer from inadequate clinical studies demonstrating significanteffects in insomnia patients, as well as potentially dangerous sideeffects. A large need exists, therefore, for a safe, effective,non-invasive, non-pharmaceutical device for the treatment of insomnia.

Recent advances have been made in the neurobiology of sleep and in theneurobiology of insomnia that can inform innovative treatments forinsomnia. Considerable evidence suggests that sleep may serve arestorative function. An EEG marker of sleep homeostasis is EEG spectralpower in the delta frequency range (1-4 Hz). The homeostatic sleep drivemay involve the restoration of brain energy metabolism through thereplenishment of brain glycogen stores that are depleted duringwakefulness. This function may have some regional specificity. A frontaldominance of EEG spectral power in the delta EEG spectral power rangehas been reported. A frontal predominance for the increase in deltapower following sleep loss has also been reported. This region of cortexplays a prominent role in waking executive functions which arepreferentially impaired following sleep deprivation. Evidence such asthis, suggests that sleep is essential for optimal executive behaviorand that the mechanism involves the frontal cortex.

“Hyperarousal”, on a variety of physiological levels, represents thecurrent leading pathophysiological model of insomnia. Insomnia patientshave been shown to have increased whole brain metabolism across wakingand sleep in relation to healthy subjects; resting metabolic rate, heartrate and sympathovagal tone in HRV, cortisol secretion in the eveningand early sleep hours, beta EEG activity during NREM sleep, increasedlevels of cortical glucose metabolism, especially in the frontal cortex,associated with higher levels of wakefulness after sleep onset,impairments in the normal drop in core body temperature around the sleeponset period; and cognitive hyperarousal resting on the pre-sleepthoughts of insomnia patients, often described as “racing,” unstoppable,and sleep-focused. Recent evidence also suggests that insomnia sufferersdemonstrate selective attention directed toward sleep and bed-relatedstimuli, which may lead to a self-reinforcing feedback loop ofconditioned arousal, poor sleep, and impaired waking function. Insomniapatients have demonstrated increases in beta EEG spectral power thatcorrelate with increased metabolism in the ventromedial prefrontalcortex during NREM sleep. Improvements in sleep in insomnia patientshave been associated with improvements in prefrontal cortex function asmeasured by functional neuroimaging.

A decline in metabolism in the prefrontal cortex, therefore, appears tobe important for the normal function of sleep and hypermetabolism inthis region may interfere with this normal function of sleep in insomniapatients. Interventions designed to reduce elevated metabolism in theprefrontal cortex may improve sleep in insomnia patients.

Several lines of evidence suggest that application of a cooling stimulusto the scalp may reduce metabolism in the cortex underlying thestimulus. Studies have shown that the application of a cooling stimulusto the scalp decreases brain temperature in the underlying cortex inboth animals and humans. In a study in pigs, even a mild surface coolingof 15 degrees C. was associated with cooling of the scalp andsuperficial brain to 35 degrees C. In this study, there was a notabledifferential effect of surface cooling on superficial vs. deep braintissue, with superficial brain tissue cooled to a greater degree thandeep brain tissue. In a human study, Wang et al were able to decreasesurface brain temperatures by an average of 1.84 degrees C. within 1hour of subjects wearing a whole head cooling helmet. Biomedicalengineering models demonstrate that cooling of the brain gray matter canbe achieved by selective head cooling on the surface. These lines ofevidence support the concept that application of a cooling stimulus atthe scalp will be associated with reductions in metabolism in theunderlying cortex.

Cerebral hypothermia is an intervention that has previously been used totreat other medical disorders due to its neuroprotective effects.Therapeutic hypothermia after global and focal ischemic and otherneurotoxic events such as head trauma, stroke and neuronal insult duringcardiopulmonary surgery has shown beneficial results in controlledanimal and human studies. Preclinical studies have shown manyneuroprotective effects of brain cooling. These include: metabolism, pH,neurotransmitter levels, free fatty acids, blood-brain bather, edema,glucose metabolism, cerebral blood flow, free radical activation, lipidperoxidation, calcium accumulation, protein synthesis, protein kinase-Cactivity, leukocyte accumulation, platelet function, NMDA neurotoxicity,growth factors, cytoskeletal proteins, calcium-dependent proteinphosphorylation, heat shock protein, immediate early genes, NOSactivity, and MMP expression. It is conceivable that the neuroprotectivebenefits of cerebral hypothermia may aid patients with sleep disorders,including insomnia. Pathophysiologic models of the adverse eventsassociated with sleep disorders are beginning to focus on the potentialneuronal toxicity of having a sleep disorder. That this may occur ininsomnia is suggested by findings of hypercortisolemia in insomniapatients in the evening and early hours of sleep and known adverseeffects of hypercortisolemia on neuronal function. One preliminary studyhas demonstrated reduced volumes of the hippocampus in insomniapatients. This may be the result of neurotoxic factors.

Reducing hypermetabolism in the frontal cortex of insomnia patientsduring both the pre-sleep period and during sleep may reduce cognitivehyperarousal reported by insomnia patients. Cerebral localization ofthis is hypothesized to occur in the prefrontal cortex given its role inexecutive function and ruminative cognitions.

Application of a cooling stimulus to the frontal scalp area may alsofacilitate the normative changes in thermoregulation associated withsleep onset. Heat loss, via selective vasodilatation of distal skinregions (measured by the distal minus proximal skin temperature gradient(DPG), seems to be a crucial process for the circadian regulation ofcore body temperature (CBT) and sleepiness. Increased DPG before lightsoff has been noted to promote a rapid onset of sleep, suggesting a linkbetween thermoregulatory and arousal (sleepiness) systems. As notedabove, impairments in the normal drop in core body temperature aroundthe sleep onset period has been demonstrated in insomnia patients. Adevice that produces heat loss, especially through the periphery,therefore, may improve sleep in insomnia patients.

Recent studies show that difficulty sleeping can be associated withincreased brain metabolic activity especially in the frontal cortex.Patent application Ser. No. 11/788,694, filed Apr. 20, 2007, titled“Method and Apparatus of Noninvasive, Regional Brain Thermal Stimuli forthe Treatment of Neurological Disorders,” now U.S. Pat. No. 8,236,038,which was previously incorporated by reference, described a method andapparatus of noninvasive, regional brain thermal stimuli for thetreatment of neurological disorders. Functional neuroimaging studieshave shown that a noninvasive device applying a hypothermic stimulus tothe scalp overlying the frontal cortex of the brain (“frontalhypothermia”) reduced cerebral metabolic activity in insomnia patientsduring sleep, especially in the frontal cortex underlying thehypothermic pad. While these studies suggest that frontal hypothermiamay be helpful in the clinical management of insomnia patients, the mostappropriate parameters for the application of the device have not yetbeen fully worked out.

Preliminary data using frontal hypothermia suggests that it reducesrelative metabolism in a region of cerebral cortex underlying the scalpwhere the device is applied. Application of the device would notnecessarily be limited to the condition of insomnia, but could beapplied to diverse neuropsychiatric disorders, each of which may haveinsomnia as a contributing component or which may be characterized byits own abnormal pattern of cerebral metabolism.

Several disorders have been shown to have insomnia as a co-morbidcondition and/or relatively specific alterations in cerebral metabolismthat may benefit from treatment with a frontal hypothermia device. Theseco-morbid conditions make medication treatment even more difficult,because these patients are often already on multiple other medications,some of which have sleep effects themselves. Co-morbid insomnia itselfhas been little studied with any form of treatment. Depression isassociated with severe sleep disturbances including difficulty fallingasleep, difficulty staying asleep, early morning awakening, ornonrestorative sleep. Functional neuroimaging studies have shownalterations in the normal reduction in prefrontal cortex metabolism fromwaking to NREM sleep. The lifetime prevalence of depression in theUnited States is 17.1% or currently 52 million individuals suggestingthat this is a significant problem. The neurobiology of sleep problemsin patients with chronic pain share significant overlaps with those ofinsomnia suggesting another medical disorder that may benefit from thefrontal hypothermia device. The most common causes of pain that disruptsleep include back pain (cost to society estimated to exceed $100billion each year), headaches (50% of whom sleep disturbances triggerheadaches and 71% of migraine sufferers have migraines that awaken themfrom sleep), fibromyalgia, and arthritis (osteoarthritis, rheumatoidarthritis and autoimmune diseases such as lupus). Chronic painprevalence estimates in the United States are 10.1% for back pain, 7.1%for pain in the legs/feet, 4.1% for pain in the arms/hands, and 3.5% forheadache. Chronic regional and widespread pain, are reported by 11.0%and 3.6% of respondents, respectively. Based on US Census data, thiswould translate into an additional market of over 50 millionindividuals. 70-91% of patients with post-traumatic stress disorder(PTSD) have difficulty falling or staying asleep. Medical treatments forthe sleep problems in PTSD have revolved around medication management,which have associated adverse events. Studies conducted as part of theNational Comorbidity Survey (NCS) have reported the prevalence oflifetime PTSD in the United States as 7.8 percent or currently a marketof over 23 million individuals.

Aside from a primary, stand alone therapy for insomnia, this device mayalso benefit insomnia patients who are partial responders to traditionalsedative-hypnotic therapy for insomnia or from cognitive-behaviortherapy for insomnia. While clinical trial data suggest that approvedhypnotics show statistically significant improvements in about ⅔rds ofpatients, significantly fewer patients report full remission ofsymptoms. This suggests that about ⅔rds of patients who are prescribedhypnotics would be non-responders or partial responders to thesetreatments and as such may benefit from adjunctive therapy with frontalhypothermia insomnia device, such as the devices and systems describedherein.

Thus, there is a substantial need to provide methods, devices andsystems for effectively creating frontal hypothermia to treat insomnia.The methods, devices and systems described herein may address many ofthe needs and issues described above.

SUMMARY OF THE DISCLOSURE

In general, described herein are methods, devices and systems forapplying hypothermal therapy within highly controlled parameters to theskin over the prefrontal cortex in order to cool the prefrontal cortexand thereby reduce metabolism of this brain region. As described ingreater detail below, hypothermic therapy of the prefrontal cortex mayameliorate insomnia. Thus, in many of the therapeutic methods describedherein, a device or system includes an applicator having a thermaltransfer region (e.g., pad, etc.) that is configured to contact, or beplaced in thermal contact, with the patient's skin; specifically theskin over the prefrontal cortex. The applicator may be a mask orgarment, and the thermal transfer region may be cooled and temperaturecontrolled by any appropriate means, including fluid cooled (e.g., watercooled) or solid-state (e.g., Peltier device) or some combinationthereof.

For example, described herein are methods of treating insomnia bynon-invasively applying hypothermal therapy to a subject's frontalcortex. The methods may include the steps of: positioning an applicatorcomprising a thermal transfer region in communication with the subject'sskin over the prefrontal cortex; cooling the thermal transfer region toa first temperature consisting of the lowest temperature that may betolerated by the subject without resulting in discomfort or arousal fromsleep; maintaining the first temperature for a first time periodextending at least 15 minutes prior to a target good night time; andmaintaining a second temperature for a second time period extending atleast 15 minutes after the target good night time.

In some variations, the first temperature is between about 10° C. andabout 18° C. In some variations, the first temperature (the coolesttolerable temperature) corresponds to the coolest temperature that maybe applied by the applicator when worn by the subject and not causeirritation (or arousal); this temperature may be empirically orexperimentally determined. For example, the method may include a step ofdetermining the first temperature for the subject.

The step of positioning the applicator may include securing theapplicator in position. For example, the applicator may be held inposition by straps. In some variations the applicator is adhesivelysecured. In general, the step of positioning the applicator may includesecuring the applicator over just the subject's forehead region. In somevariations the applicator is limited to the forehead region.

In some variations the step of cooling the thermal transfer region to afirst temperature comprises ramping (including gradually ramping) thetemperature of the thermal transfer region from ambient temperature tothe first temperature over at least five minutes, ten minutes, 15minutes, etc.

The step of maintaining the first temperature may comprise holding thethermal transfer region at the first temperature for at least 30minutes, one hour, etc.

In some variations the first temperature is the same temperature as thesecond temperature (e.g., between 10° C. and 18° C.). However, in somevariations the method includes the step of changing the temperature ofthe thermal transfer region to the second temperature. In general, thesecond temperature may be a temperature between the first temperatureand 30° C. For example, the second temperature may be between about 20°C. and about 25° C. The step of maintaining a second temperature for thesecond time may comprise maintaining the second temperature for morethan one hour, 2 hours, 3 hours, 4 hours, 6 hours, 8 hours, or theentire sleep period. In some variations, the method further comprisesadjusting the second temperature based on patient sleep-cycle feedback.

Also described herein are methods of treating insomnia by non-invasivelyapplying hypothermal therapy to a subject's frontal cortex, the methodcomprising: positioning an applicator comprising a thermal transferregion in communication with the subject's skin over the prefrontalcortex; cooling the thermal transfer region to a first temperatureconsisting of the lowest temperature that may be tolerated by thesubject without resulting in discomfort or arousal from sleep;maintaining the first temperature for at least 15 minutes prior to atarget good night time; maintaining the first temperature for at least30 minutes after the target good night time; and maintaining thetemperature at a second temperature between the first temperature and30° C. for at least 30 minutes.

Also described herein are methods of reducing sleep onset bynon-invasively applying hypothermal therapy to a subject's frontalcortex, the method comprising: positioning an applicator comprising athermal transfer region in communication with the subject's skin overthe prefrontal cortex; cooling the thermal transfer region to a firsttemperature between about 10° C. and about 18° C.; and maintaining thefirst temperature for a first time period extending at least 15 minutesprior to a target good night time.

Also described herein are methods of sustaining sleep in a subject bynon-invasively applying hypothermal therapy to the subject's frontalcortex, the method comprising: positioning an applicator comprising athermal transfer region in communication with the subject's skin overthe prefrontal cortex; after a target good night time, maintaining thethermal transfer region at a first temperature consisting of the lowesttemperature that may be tolerated by the subject without resulting indiscomfort or arousal from sleep; and maintaining the first temperaturefor a first time period extending at least 30 minutes after the targetgood night time. For example, the first temperature may be between about10° C. and about 18° C.

In general the methods of treating insomnia (e.g., by decreasing sleeplatency and/or by increasing sustained sleep may be performed bynon-invasive cooling, and particularly by cooling the skin over thefrontal cortex. In some variations, this cooling is limited to foreheadregion. The systems and devices described herein generally control theprofile of the hypothermal therapy applied so that both the temperatureand timing of the dosage is controlled. The system may be configured toapply complex dosing regimens and may be further configured to modify orselect the dosing regimen based on feedback from the patient. Feedbackmay be patient selected (e.g., by adjusting or changing a control input)or may be based of one or more sensors detecting physiologicalparameters from the patient, such as sleep level, REM/NREM state, or thelike.

As described in greater detail below the devices and systems forapplying hypothermal therapy as described herein generally include anapplicator (e.g., to be secured to or worn by the subject) having athermal transfer region. The thermal transfer region is cooled. Thethermal transfer region is also placed in contact with the skin over thesubject's frontal cortex. In general, the applicator and thermaltransfer region are configured so that the subject may comfortably andsafely wear the device while sleeping or before sleeping (to increasedrowsiness). The overall system may be configured to be quiet (so as notto disrupt sleep), and may include one or more controllers forregulating the temperature of the thermal transfer region, as mentionedabove. The controller may be a microcontroller (including dedicatedhardware, software, firmware, etc.). In some variations the system isconfigured to be worn by the subject every night, and thus may include awashable, disposable, or replaceable skin-contacting region. Forexample, the thermal transfer region may be covered by a disposablematerial or cover that can be replaced nightly with each use. In somevariations one or more sensors may also be included to receive patientinformation and/or performance information on the system; thisinformation may be provided to the controller and may be used toregulate the temperature. Overall, the system may be lightweight andeasy to use.

Other features of the invention described herein are outlined below ingreater detail, and with reference to the figures.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a graph illustrating the increase in whole brain metabolismin insomnia during waking and sleep. FIG. 1B illustrates brain regionswhere insomnia patients do not show as great of a decline in relativemetabolism from waking to sleep. FIG. 1C shows brain regions whererelative metabolism is decreased in insomnia patients.

FIG. 2A is a graph illustrating change in the average core bodytemperature over time in patients treated and un-treated using localizedfrontal hypothermia treatment.

FIG. 2B shows PET scans of an insomniac patient undergoing treatmentusing frontal hypothermia and illustrating a reversal of prefrontalhypermetabolism.

FIG. 3A shows a graph illustrating the decrease in subjective arousal ininsomniac patients treated with prefrontal hypothermia as describedherein.

FIG. 3B shows a graph illustrating a decrease in whole brain metabolism(compared to control) in patients treated with prefrontal hypothermia.

FIG. 3C shows a graph illustrating the increase in subjective sleepinessin insomniac patients treated with prefrontal hypothermia.

FIG. 3D shows a graph illustrating the decrease a reduction in wakingafter sleep onset in patients treated with prefrontal hypothermia.

FIG. 3E is a graph illustrating an increase in delta power during sleepin patients treated with prefrontal hypothermia.

FIG. 3F is a side-by-side comparison of PET scans showing a reduction inregional metabolism in patients treated with prefrontal hypothermia.

FIG. 4A shows one variation of a headpiece of a device for applyinghypothermia.

FIG. 4B illustrates the headpiece applied to a subject's head.

FIG. 5A shows the effect of one variation of a device for applyingprefrontal hypothermia on sleep onset latency in an insomniac patientcompared to non-insomniac.

FIG. 5B shows the effect of one variation of a device for applyingprefrontal hypothermia on awake after sleep onset in an insomniacpatient compared to non-insomniac.

FIG. 5C shows the effect of one variation of a device for applyingprefrontal hypothermia on wakefulness in the first half of the night inan insomniac patient compared to non-insomniac.

FIG. 5D shows the effect of one variation of a device for applyingprefrontal hypothermia on wakefulness in the second half of the night inan insomniac patient compared to non-insomniac.

FIG. 5E shows the effect of one variation of a device for applyingprefrontal hypothermia on total sleep time in an insomniac patientcompared to non-insomniac.

FIG. 5F shows the effect of one variation of a device for applyingprefrontal hypothermia on sleep efficiency in an insomniac patientcompared to non-insomniac.

FIG. 5G shows the effect of one variation of a device for applyingprefrontal hypothermia on the percentage of stage 1 sleep in aninsomniac patient compared to non-insomniac.

FIG. 5H shows the effect of one variation of a device for applyingprefrontal hypothermia on the percentage of stage 2 sleep in aninsomniac patient compared to non-insomniac.

FIG. 5I shows the effect of one variation of a device for applyingprefrontal hypothermia on the percentage of stages 3/4 sleep in aninsomniac patient compared to non-insomniac.

FIG. 5J shows the effect of one variation of a device for applyingprefrontal hypothermia on the percentage of REM sleep in an insomniacpatient compared to non-insomniac.

FIG. 5K shows the effect of one variation of a device for applyingprefrontal hypothermia on the number of whole night delta counts in aninsomniac patient compared to non-insomniac.

FIG. 5L shows the effect of one variation of a device for applyingprefrontal hypothermia on the whole night spectral power in an insomniacpatient compared to non-insomniac.

DETAILED DESCRIPTION

As describe above, it has been suggested that the restorative aspects ofsleep can be linked regionally with heteromodal association cortex,especially in the frontal regions. The studies described herein clarifythe regional cerebral metabolic correlates of this. In the first study,changes in regional cerebral metabolism that occur between waking andsleep in healthy subjects were identified. Fourteen healthy subjects(age range 21 to 49; 10 women and 4 men) underwent concurrent EEG sleepstudies and [18F]fluoro-2-deoxy-D-glucose ([18F]-FDG) positron emissiontomography (PET) scans during waking and NREM sleep. Whole brain glucosemetabolism declined significantly from waking to NREM sleep. Relativedecreases in regional metabolism from waking to NREM sleep were found inheteromodal frontal, parietal and temporal cortex, and in dorsomedialand anterior thalamus. These findings are consistent with a restorativerole for NREM sleep largely in cortex that subserves essential executivefunction in waking conscious behavior. In the second study, changes inregional cerebral metabolism were identified that occur between usualNREM sleep and recovery NREM sleep following a night of sleepdeprivation. In this study, homeostatic sleep need, or sleep drive, wasmodulated in a within-subjects design via sleep deprivation. Four youngadult healthy male subjects (mean age+s.d.=24.9±1.2 years) received NREMsleep using [18F]fluoro-2-deoxy-D-glucose positron emission tomography([18F]-FDG PET) assessments after a normal night of sleep and againafter 36 hours of sleep deprivation. Both absolute and relative regionalcerebral glucose metabolic data were obtained and analyzed. In relationto baseline NREM sleep, subjects' recovery NREM sleep was associatedwith: (1) increased slow wave activity (an electrophysiological markerof sleep drive); (2) global reductions in whole brain metabolism; and(3) relative reductions in glucose metabolism in broad regions offrontal cortex, with some extension into parietal and temporal cortex.The results demonstrate that the homeostatic recovery function of sleepfollowing sleep deprivation is associated with global reductions inwhole brain metabolism as well as greater relative reductions in broadregions of largely frontal, and related parietal and temporal cortex. Inother words, sleep deprivation accentuates the decrease in brainmetabolism normally seen during NREM sleep. Thus, a medical device thatalters metabolism in a pattern similar to that seen in healthy sleep orrecovery sleep following sleep deprivation may benefit insomniapatients.

To test this hypothesis, a study of insomnia patients was performed toinvestigate how these normal changes in brain metabolism becomedisturbed in insomnia patients. Insomnia patients and healthy subjectscompleted regional cerebral glucose metabolic assessments during bothwaking and NREM sleep using [18F]fluoro-2-deoxy-D-glucose positronemission tomography (PET). Insomnia patients showed increased globalcerebral glucose metabolism during sleep and wakefulness, as shown inFIG. 1A. A group x state interaction analysis confirmed that insomniasubjects showed a smaller decrease than did healthy subjects in relativemetabolism from waking to NREM sleep in the ascending reticularactivating system, hypothalamus, thalamus, insular cortex, amygdala andhippocampus and in the anterior cingulate and medial prefrontal cortices(as shown in FIGS. 1B and 1C). While awake, in relation to healthysubjects, insomnia subjects showed relative hypometabolism in a broadregion of the frontal cortex bilaterally, left hemispheric superiortemporal, parietal and occipital cortices, the thalamus, hypothalamusand brainstem reticular formation. This study demonstrated thatsubjectively disturbed sleep in insomnia patients is associated withincreased brain metabolism. The inability of the insomniac patients tofall asleep may be related to a failure of arousal mechanisms to declinein activity from waking to sleep. Further, their daytime fatigue mayreflect decreased activity in prefrontal cortex that results frominefficient sleep. These findings suggest interacting neural networks inthe neurobiology of insomnia. These include a general arousal system(ascending reticular formation and hypothalamus), an emotion regulatingsystem (hippocampus, amygdala and anterior cingulate cortex), and acognitive system (prefrontal cortex). Notably, ascending arousalnetworks are functionally connected to cortical regions involved incognitive arousal at the cortical level which can feedback and modulatemore primitive brainstem and hypothalamic arousal centers. A medicaldevice that alters metabolism in one or more portions of this networkcould benefit insomnia patients and produce more restful sleep.

A second study in insomnia patients was conducted to clarify thecerebral metabolic correlates of wakefulness after sleep onset (WASO) inprimary insomnia patients testing the hypothesis that insomnia subjectswith more WASO would demonstrate increased relative metabolismespecially in the prefrontal cortex given the role of this region of thebrain in restorative sleep and in cognitive arousal. Fifteen patientswho met DSM-IV criteria for primary insomnia completed 1-week sleepdiary (subjective) and polysomnographic (objective) assessments of WASOand regional cerebral glucose metabolic assessments during NREM sleepusing [18F]fluoro-2-deoxy-D-glucose positron emission tomography (PET).Both subjective and objective WASO positively correlated with NREMsleep-related cerebral glucose metabolism in the pontine tegmentum andin thalamocortical networks in a frontal, anterior temporal, andanterior cingulate distribution. These effects may result from increasedactivity in arousal systems during sleep and/or to activity in higherorder cognitive processes related to goal-directed behavior, conflictmonitoring, emotional awareness, anxiety and fear. These processes arethought to be regulated by activity of the prefrontal cortex. A medicaldevice that facilitates the normal reduction in relative metabolism inthe prefrontal cortex during sleep could benefit insomnia patients.

As described above, cerebral hypothermia has been utilized in othermedical disciplines as a means to reduce metabolic activity in thebrain. Theoretical models suggest that application of a cooling stimulusat the scalp surface will cool and subsequently reduce metabolism in theunderlying superficial cortex. These observations raised the possibilitythat a medical device that produced regional cooling to the scalp overthe area of the prefrontal cortex, may reduce the hypermetabolism inthat region in insomnia patients, allowing them to transition to sleepmore easily and to subsequently obtain more restful sleep across thenight. It is also conceivable that these cortical effects may havedownstream effects on brainstem and hypothalamic centers ofsleep/arousal regulation.

A device was constructed to test the application of hypothermia appliedto the skin over the prefrontal cortex as a method of treating insomniaand sleep-related phenomena. The device itself included a custom sizedheadpiece to fit the area of the scalp over the frontal cortex thatcirculated varying temperature fluids and a programmable coolingchamber/pump that provided the cooling and power for circulating thefluid to the headpiece. A study was performed to determine if the devicelowered cerebral metabolism in the prefrontal cortex in insomniapatients. The study compared an active treatment (device at 14° C.) vs.a normothermic device comparison (control). Outcome measures includedregional cerebral metabolism during sleep as measured by [18F]-FDG PET.148 subjects were screened, 12 completed sleep studies, and 8 completedall PET imaging studies. The data showed that the device reducedcerebral metabolism especially in the prefrontal cortex underneath thedevice. FIGS. 2A and 2B illustrate some of the findings, and show trendstowards reductions in whole brain metabolism, reductions in relativeregional metabolism (highlighted regions of FIG. 2B), especially in theprefrontal cortex, an increase in sleepiness and reduction in arousalwhile the device was worn for 60 minutes prior to bedtime, reductions inminutes of waking, increases in EEG delta spectral power and a reductionin core body temperature around the sleep onset period (FIG. 2A).

FIGS. 3A-3F illustrate some of the additional findings of this work. Thestudy used to achieve these results and the design parameters for thisstudy are described in greater detail below.

Significantly and surprisingly, 9 of 12 (75%) insomnia patients reportedpositive subjective effects of the device. All subjects encouragedfurther development of the device based on their experiences and allsubjects easily understood/accepted the therapeutic concept for thetreatment of their insomnia. They also reported: (1) a clear preferencefor the device over pills; (2) the device decreased distracting thoughtsprior to getting in to bed; (3) the device facilitated sleepmaintenance; (4) they experienced a subjective surprise that sleeppassed without awareness; and (5) their sleep felt refreshing.

As illustrated in FIG. 3A, the subjective arousal of patients treatedwith frontal/prefrontal hypothermia therapy decreased while wearing thedevice prior to getting into bed. In FIG. 3A, the x axis represents the60 minute period prior to the subject getting into bed while wearing thedevice. The y-axis represents a subjective assessment of arousal (0=noarousal, 3=maximal arousal) measured in 15 minute increments up untilthe time that the patient got into bed. FIG. 3B shows a graphillustrating a decrease in whole brain metabolism measured by PET scansduring NREM sleep between two conditions, an active condition (wearingthe device at 14 degrees C. for 60 minutes prior to getting into bed andcontinuing during sleep until the time of measurement at 20-40 minutesfollowing sleep onset) and a control condition (wearing the device at athermoneutral 30 degrees C. for 60 minutes prior to getting into bed andcontinuing during sleep until the time of measurement at 20-40 minutesfollowing sleep onset) in primary insomnia patients. FIG. 3C shows agraph illustrating the increase in subjective sleepiness in insomniacpatients treated with prefrontal hypothermia. In FIG. 3C, the x axisrepresents the 60 minute period prior to the subject getting into bedwhile wearing the device. The y-axis represents a subjective assessmentof sleepiness (0=no sleepiness, 3=maximal sleepiness) measured in 15minute increments. FIG. 3D shows a graph illustrating the reduction inminutes of waking after sleep onset for the first 40 minutes of sleepduring two conditions, an active condition (wearing the device at 14degrees C. for 60 minutes prior to getting into bed and continuingduring sleep for 40 minutes of measurement) and a control condition(wearing the device at a thermoneutral 30 degrees C. for 60 minutesprior to getting into bed and continuing during sleep for 40 minutes ofmeasurement) in primary insomnia patients. FIG. 3E shows a graphillustrating the increase in automated EEG delta power (y-axis) duringthe first 40 minutes of NREM sleep between two conditions, an activecondition (wearing the device at 14 degrees C. for 60 minutes prior togetting into bed and continuing during sleep until the end time ofmeasurement at 40 minutes) and a control condition (wearing the deviceat a thermoneutral 30 degrees C. for 60 minutes prior to getting intobed and continuing during sleep until the end time of measurement at 40minutes) in primary insomnia patients. FIG. 3F shows the results of acomparison of regional cerebral metabolism during NREM sleep between twoconditions, an active condition (wearing the device at 14 degrees C. for60 minutes prior to getting into bed and continuing during sleep untilthe time of PET measurement at 20-40 minutes following sleep onset) anda control condition (wearing the device at a thermoneutral 30 degrees C.for 60 minutes prior to getting into bed and continuing during sleepuntil the time of PET measurement at 20-40 minutes following sleeponset) in primary insomnia patients. The brain regions highlighted inblue on two different sections through the brain show the areas of thebrain, especially in the frontal cortex in the area underneath thedevice placement, where metabolism was significantly decreased in theactive condition vs. the control condition.

Further studies were performed to determine the tolerability andefficacy of a medical device that delivers frontal hypothermia for anextended period (e.g., all night) for the treatment of insomnia. Thesestudies were also performed to further define the specific thermalenergy transfer parameters associated with treatment efficacy.

Data comparing subjective and objective measures of sleep, andtolerability in mid-life insomnia patients across 4 frontal hypothermiaintervention conditions were collected. These included two active andone neutral “doses” of frontal hypothermia device temperature settingsand a no device control as follows: (1) a “no device” control; (2) adevice at “thermo-neutral” 30° C. and flow rate of 7 gallons per hour;(3) a device at 22° C. and flow rate of 7 gallons per hour; and (4) adevice at 14° C. and flow rate of 7 gallons per hour. Based on the flowrates of the active doses, thermal energy will be drawn off of theforehead at a thermal transfer rate ranging from 10-25 W (power). Thesurface area of the applicator for the experimental device (e.g., theheadpiece) is shown in FIGS. 4A and 4B.

Twelve insomnia patients were entered into this study. Each interventionwas applied for two nights' duration, separated by at least 2 nightsnon-intervention sleep at home. The order of presentation of conditionswas randomized across subjects in order to control for adaptation andcarry over effects from one condition to the next. Primary inclusioncriteria included DSM-IV diagnosis of primary insomnia; ages 18-65 (agerange minimizes effects of aging on sleep and regional cerebralmetabolism that could confound interpretation of studies whileencompassing the most prevalent ages for insomnia). Subjects remainedalcohol-free and avoided drugs that could affect sleep. Insomnia wasdefined according to the “General Insomnia Criteria” set forth in theInternational Classification of Sleep Disorders, 2nd Edition and thecriteria for “Insomnia Disorder” in the Research Diagnostic Criteria forInsomnia. These criteria require: (1) a complaint of difficulty fallingasleep, staying asleep, awakening too early, or nonrestorative sleep;(2) adequate opportunity for sleep; and (3) evidence for at least onetype of daytime impairment related to the sleep complaint. By setting aminimum duration criterion of at least one month and requiring the sleepcomplaints to be present on most days, we were also consistent withcriteria for “Primary Insomnia” in the Diagnostic and Statistical Manualof Mental Disorders, 4th Edition. In order to insure a minimum level ofoverall severity and comparability with other published data, werequired that insomnia participants score >14 on the Insomnia SeverityIndex. Further, we required that their screening and baseline sleepdiaries demonstrate wakefulness after sleep onset of >30 minutes andsleep efficiency <85% on at least 50% of nights, which is consistentwith the diagnostic criteria above, and with recommendations forquantitative insomnia criteria.

Primary exclusion criteria included neuropsychiatric disorders that mayindependently affect sleep, brain function or cognition, such as currentmajor syndromal psychiatric disorders, including DSM-IV mood, anxiety,psychotic, and substance use disorders. Specific exclusionary diagnosesincluded major depressive disorder, dysthymic disorder, bipolardisorder, panic disorder, obsessive compulsive disorder, generalizedanxiety disorder, any psychotic disorder, and any current substance usedisorder. Subjects were not excluded for subsyndromal symptoms ordisorders in these domains (e.g., minor depression, limited symptompanic attacks). We did not exclude subjects for simple phobia, socialphobia, past eating or substance use disorders, specific learningdisabilities, or personality disorders. Psychiatric disorders wereevaluated using the Structured Clinical Interview for DSM-IV (SCID).Other exclusion criteria include: unstable medical conditions includingsevere cardiac, liver, kidney, endocrine (e.g. diabetes), hematologic(e.g. porphyria or any bleeding abnormalities), other impairing orunstable medical conditions or impending surgery, central nervous systemdisorders (e.g., head injury, seizure disorder, multiple sclerosis,tumor), active peptic ulcer disease, inflammatory bowel disease, andarthritis. Individuals with well-controlled health conditions that donot affect sleep or well-being (e.g., well-controlled thyroid disorders,asthma, or ulcer) were not excluded. We excluded women who werepregnant, nursing, or sexually active but not using an effective methodof birth control. Subjects who met inclusion criteria and did not haveany specific exclusion criteria also had a complete medical history andphysical examination, conducted by a physician's assistant, and a set ofroutine laboratory tests to rule out any unsuspected medical conditions.Specific tests included fasting glucose, complete blood count, liverfunction tests, serum chemistry, thyroid function tests, urinalysis, andurine drug screen to examine surreptitious sedative use. Other exclusioncriteria included: irregular sleep schedules; an AHI (apnea hypopneaindex) >20 and oxyhemoglobin desaturations <90% for at least 10% of thenight from a diagnostic sleep study; use of medications known to affectsleep or wake function (e.g., hypnotics, benzodiazepines,antidepressants, anxiolytics, antipsychotics, antihistamines,decongestants, beta blockers, corticosteroids); or consumption of morethan one alcoholic drink per day, or more than 7 drinks per week.

Subjects were asked to report to the sleep laboratory about 2-3 hoursprior to their usual good night time (GNT) for 2 consecutive nights on 4separate occasions, each separated by at least 2 days. After beingstudied throughout the night on each night, subjects were allowed toleave the sleep lab after awakening each morning until returning thefollowing evening. On arrival at the sleep lab, subjects were preparedfor their studies as follows. Subjects first ingested a temperaturemonitoring pill (described below) along with their last drinks of fluid.Subjects will remain n.p.o. for the next 3 hours, then allowed water ona p.r.n. basis for the remainder of the study. They were fitted with abelt pack that included a monitoring device to receive the signal fromthe pill. Subjects were fitted with electrodes and thermistors formonitoring polysomnography, EKG and skin temperature as described below.About 60 minutes prior to good night time (GNT), subjects were seated ina comfortable chair in a sleep lab bedroom. At that time, they filledout questionnaires and rating scales (described below). From the end ofcompletion of questionnaires until 45 minutes prior to GNT (GNT forsubjects in the no device condition), technicians ensured that allrecording equipment was registering appropriate signals, then at 45minutes prior to GNT (except for the no device condition), they appliedthe temperature controlling forehead pad (described below) at atemperature of 30 degrees Celsius (normothermia). After application ofthe temperature controlling forehead pad, the technician then set thewater bath temperature to the desired endpoint for that night's study(14, or 22, or 30 degrees Celsius) where it remained for the remainderof the night of sleep. Equilibration to the desired temperature occurredafter 10-15 minutes. Subjects completed rating scales as defined belowafter the device had been applied, then every 15 minutes until GNT.After completion of the last rating scales at GNT, subjects were askedto get in to bed to sleep undisturbed with monitoring electrodes andthermistors in place for the remainder of the night until their habitualgood morning time (GMT). At that time, recording devices and the frontalhypothermia device were removed, morning questionnaires includingpost-sleep evaluations and subjects were free to leave for the day untilreturning for the next night's study.

Temperature doses were randomized for the study. The water bathtemperatures on the three device interventions included: 14, 22 and 30°Celsius. The flow rate through the mask was 7 gallons per hour at thethermal transfer rate ranging from 10-25 W (power). The lowertemperature (about 14° C.) was determined as the limit to which a coldstimulus is experienced by subjects to be cold, yet not uncomfortablycold to the point of producing discomfort. The 30° C. temperature waschosen as a temperature experienced by subjects as “neutral”, i.e. notcool or warm, and the 22° C. temperature was chosen as halfway betweenthese two to provide one additional temperature range. To eliminate anyorder effects of application, the ordering of the three temperatureconditions of the frontal hypothermia water bath and the no devicecondition was randomized across subjects. Preliminary studies show theseranges of temperatures to be well tolerated and without adverse events.

Polysomnography was monitored while frontal hypothermia or no device wasapplied on each night in the sleep lab. EEG sleep was monitored acrossthe night while subjects slept from GNT to GMT to assess effects ofdifferent temperature levels of frontal hypothermia on measures of sleeplatency, sleep maintenance and delta EEG spectral power duringsubsequent sleep. The polysomnographic EEG montage for all thesepurposes consisted of a single EEG channel (C4/A1-A2), bilateral EOGsreferenced to A1-A2, and bipolar submental EMG. Manual and automatedscoring of the EEG was performed with emphasis on EEG spectral power inthe theta and delta frequency bands as measures of arousal and depth ofsleep.

The sleep montage on a sleep disorder screening night conducted prior toany other night of sleep, consisted of a single EEG channel (C4/A1-A2),bilateral EOGs referenced to A1-A2, bipolar submental EMG(electromyogram), single-lead EKG (electrocardiogram), and anteriortibialis EMG. Nasal airflow was monitored by the nasal pressuretransducer technique consisting of a standard nasal cannula for O₂delivery, but instead of being attached to an O₂ source, it was attachedto a pressure transducer to detect pressure swings at the nasal opening.Oral airflow was recorded using a thermistor positioned in front of themouth. Breathing effort was recorded by respiratory inductanceplethysmography (R.I.P.) which employed two elasticized bands, onearound the rib cage and one around the abdomen, each containing anembedded wire coil. As the circumference of the two chest wall“compartments” change with breathing effort, the embedded wires arestretched and a signal is generated. SpO₂ was non-invasively recorded inthe standard fashion by pulse oximetry (Ohmeda, Biox 3700 at fastestpossible response time).

Visual sleep stage scoring was also performed. Inter-rater reliabilityof visual sleep stage scoring was conducted quarterly by the laboratorymanager to ensure that technologists maintain consistency over time.Epoch-by-epoch agreement in sleep staging was measured monthly andcharacterized by Fleiss' modified kappa statistic, intraclasscorrelations, and absolute % agreement in epochs. Kappa values for REMand wakefulness have values >80, intraclass correlations are >0.85, and% agreement >90%. The following visually scored sleep measures wereobtained: sleep latency; time spent asleep; and sleep efficiency.

Sleep latency (SL) is the interval between Good Night Time (GNT) and thefirst epoch of 10 consecutive minutes of Stage 2-4 NREM or REM sleep,interrupted by no more than one minute of wakefulness. It is expressedin minutes. Time spent asleep (TSA) is the total time spent in any stageof NREM or REM sleep after sleep onset. It is expressed in minutes.Sleep efficiency (SE) is the ratio of time spent asleep to totalrecording period duration, multiplied by 100. It is expressed as apercentage (SE=[TSA/TRP]×100).

Power spectral analysis was used to quantify the frequency content ofthe sleep EEG from 0.25-50 Hz. Software was developed in-house toperform spectral analysis of the sleep EEG. Modified periodograms arecomputed using the Fast Fourier transform (FFT) of non-overlapping4-second epochs of the sleep EEG. One-minute EEG spectra are obtained asthe average of the artifact-free 4-second spectra for a given minute.These 1-minute spectra are time-aligned with the hand scores to allowfor the computation of average spectra for various time intervals (e.g.,the first NREM period). To further reduce the data for statisticalanalysis, the spectra can be banded as desired (e.g., a 0.5-4 Hz deltaband). This software includes an automated detection routine toeliminate high frequency (predominantly muscle) artifacts (Brunner etal., 1996). Signal processing using power spectral analysis wascompleted. Power spectral analysis was used quantify EEG power acrossthe frequency range. Power in the delta band was used as dependentmeasures across studies in the program as a whole. For example, deltapower is thought to reflect the homeostatic sleep drive that increasesexponentially as a function of prior wakefulness, decreasesexponentially during the course of NREM sleep episodes, and is reducedas a function of aging and numerous sleep disorders. Delta power isexpressed as micro V²/Hz in the 0.25-4.0 Hz frequency range during NREMsleep.

The temperature applicator (the headpiece) in this example istemperature-regulated by control of the temperature of a circulatingfluid (H₂O in this example). The temperature of the internal fluid wasmonitored and regulated in water bath connected by tubing to theheadpiece. The temperature was monitored by the water bath and convertedto a signal recorded on the polygraph.

Subject temperature was measured in part by a temperature assessing pill(Vitalsense® system) that was swallowed to record continuous core bodytemperature over the nights of study in the sleep lab. The pill used atiny radio transmitter to measure core body temperature and sent theinformation to a belt pack worn by the subject. The pill passed throughthe subject undigested and was then discarded with a bowel movement. Thedevice has been approved as safe by the U.S. Food and DrugAdministration (FDA) [510(k) number K033534]. Each night, the system waschecked for an active signal signifying that the pill had not beenpassed. If no signal was detected, a new pill was initiated andswallowed. Thermistors were also used to record skin temperature beforeand during application of frontal hypothermia at: (1) frontal scalpunderneath the pad; (2) occipital scalp; and (3) back of non-dominanthand. Thermistors measured ambient room temperature before and duringthe application of frontal hypothermia.

As mentioned, in this study the device for applying frontal hypothermiaincluded a temperature-controlling device specifically designed for thisapplication for applying frontal hypothermia. The custom coolingapparatus circulated temperature controlled water, pumped from a waterbath to a pad on the patient's forehead. The pad is custom shaped fromtwo laminated sheets of vinyl to cover the target area on the foreheadoverlaying the prefrontal cortex. The remainder of the head remaineduncovered except for a thin nylon spandex cap to retain the pad and holdthe tubing. In this exemplary system, a thin layer of hydrogel betweenthe skin and pad improved thermal conductivity and kept the pad againstthe forehead with minimal air gaps.

The device used in this study included a circulating programmablelaboratory water bath (e.g., Polyscience: Polyscience Programmable Model9112). The system was programmable. The headpiece included a customshaped vinyl laminate produced with a prescribed flow pattern (e.g., seeFIG. 4A) and a boundary matching the surface area of the head targetedfor cooling. A hydrogel adhesive may be used to hold the pad snuglyagainst the forehead without applying excessive pressure to the pad. Anadhesive may also increased the surface area for contact and provided ahigh efficiency thermal transfer surface.

In this example, the temperature applicator of the headpiece 400 wasused with a retainer device (not shown) to hold the temperatureapplicator against the subject's head. This head holder in this examplewas a thin nylon spandex cap that was placed over the laminate to keepit positioned on the head before and during sleep. The applicator 400includes a thermal transfer region (surface 402) which is configured tobe worn against the patient's forehead. As mentioned, an adhesive (e.g.,hydrogel, not shown) may be included to help form a thermal contact withthe forehead. The applicator 400 shown in FIG. 4 includes channels 405,through which cooled (cooling) thermal transfer fluid may be moved; inthis example an inlet 407 and outlet 709 may be included to pump thermaltransfer fluid through the applicator. In this example, the applicatoralso includes at least one sensor 411 comprising a thermister formonitoring the temperature of the applicator; this information may befed back to the system for regulating the temperature of the applicator.

The analyses tested differences in sleep between insomniacs andnon-insomniacs over a range of active and control temperatures offrontal hypothermia in a within-subjects design presented in arandomized order. The major group difference that was analyzed was thewithin-subject intervention study comparing the insomnia patients acrossthe various interventions. Multivariate analysis of covariance is anomnibus approach used to compare multiple measures between groups whilecontrolling for known covariates such as age and gender. A repeateddomain was added to the model to explore differences in measures acrossinterventions. The results tested whether there is a linear effect frombaseline to neutral temperature to 22° C. to 14° C. temperature of thecirculating water at identical flow rates and using identical thermaltransfer pad over the forehead. Age- and gender-matched historicalcontrol subjects' data are shown on the graphical results displayed inFIGS. 5A-5L to illustrate relationships to normative sleep.

For the 12 primary insomnia subjects examined (9 women/3 men, with amean age+s.d. of 44.62+12.5 years) compared to 12 healthy age- andgender-matched historical control subjects, the results show aremarkable effect on hypothermic treatment, particularly at lowertemperatures (closer to the 14° C. parameter). The graphs shown in FIGS.5A-5L also provide a comparison in relation to normative measures forhealthy control subjects studied in the same laboratory environment.

These results show that that the thermal effect (the hypothermic effect)applied non-invasively to the subject's skin adjacent to the prefrontalcortex has a temperature-dependent effect. This effect may also betime-dependent, in applying the therapy for a time before the GNT andfor some period after GNT, including the entire night or a portion ofthe night during sleep. The effects and parameters are illustratedbelow.

For example, the system typically applies (non-invasively) hypothermictherapy to a patient's skin above (adjacent) to the prefrontal cortexfor an extended period of time at a temperature that is not perceived asuncomfortably cold (e.g., typically greater than or about 10° C., suchas 14° C.). This therapy typically shortens the time to fall asleep, asillustrated in FIG. 5A. In FIG. 5A the sleep onset latency of insomniacpatients experiencing cooling (both moderate cooling at 22° C. andmaximum cooling at 14° C.) was significantly shorter than in untreatedsubjects. This effect was also seen to be temperature dependent; greatercooling (“max cool”) at 14° C. had a more rapid sleep onset.

In addition to helping the insomniac patient fall asleep more quickly,the system also enhanced and increased the duration of sleep, as shownin FIGS. 5B-5E, an effect which was also temperature dependent. Forexample, hypothermic treatment also diminished wakefulness after sleeponset; in FIGS. 5B, 5C and 5D, the time the insomniac patient was awakeafter onset of sleep fell to within normal controls, particularly in thefirst half of the night, as shown in FIG. 5C. Although this preliminarywork is not definitive with respect to the effect in the first half ofthe night compared to the second half, it suggests that it may besufficiently effective to provide hypothermic treatment for at least thefirst half of the night (e.g., anticipated sleep period). For example,for between about 2-6 hours, and less effective beyond that point.Alternatively, it may be beneficial to shift the temperature appliedeither up or down, later during sleep in order to further regulate thepatient's sleep.

Hypothermic treatment increased the total sleep time (as shown in FIG.5E) and increased the overall sleep efficiency to within “normal” ranges(FIG. 5F). In addition, hypothermic treatment also shifts EEG sleepstages to deeper stages of sleep, as illustrated in FIGS. 5G-5I. Inaddition, in these experiments hypothermic treatment also increases slowwave sleep toward healthy levels (FIGS. 5J-5L).

The above effects appear to be dose-dependent, particularly during theearly period of application (e.g., sleep onset and early maintenance),with increasing levels of improvement from a neutral temperature to 22°Celsius to 14° Celsius. Thus, depending on the type of sleep desired, itmay be possible to vary the temperature in a regulated manner across anight of sleep to alter sleep in a characteristic manner. Varying thetemperature may also allow decreased power requirements for the system.Feedback relaying information regarding the type of sleep achieved mayalso be used to refine the temperature algorithm in a real time manner.

Devices and Systems

Various devices and systems for applying hypothermal treatment to theskin over the prefrontal cortex are described herein. In general thesedevices include at least one thermal transfer region (e.g., thermaltransfer pad) which is configured to cool the skin above the prefrontalcortex.

The thermal transfer region may be any appropriate configuration,particularly those described below. For example, a thermal transfer padmay be shaped to cover the region of the forehead that overlies thefrontal cortex of the brain. As described above, the frontal cortex isthought to be important for producing the restorative aspects of sleepbased on sleep deprivation studies. Following sleep deprivation, theamount of slow wave sleep, a correlate of the homeostatic function ofsleep, is increased in recovery sleep. The increase in slow waves isregionally maximal in the frontal cortex. The frontal cortex has alsobeen shown to show greater reductions in metabolic activity during arecovery night of sleep following sleep deprivation than in relation toregular sleep. Cognitive deficits related to sleep deprivation have alsobeen observed to be in realms thought to be related to frontal cortexfunction. Brain imaging and EEG sleep research studies described aboveshow that application of a cooling stimulus over the forehead in a shapesimilar to that of the frontal cortex reduces metabolic activity in theunderlying frontal cortex and this is associated with an increase inslow wave sleep, reductions in sleep latency, reductions in wakefulnessafter sleep onset, an increase in the duration of sleep at night ininsomnia patients. Finally insomnia patients have been shown to haveincreased whole brain and increased frontal cortex metabolism duringsleep that is related to their tendency to wake up across a night ofsleep.

In some variations, the thermal transfer region may be part of a mask,garment, or other device that directs thermal transfer to the region ofthe scalp over the frontal cortex to benefit sleep. In some variationsthe thermal transfer region is limited to cover all or a portion of thefrontal cortex. Thus, in some variations the system is configured tolimit the region of thermal transfer to the skin region (e.g.,forehead).

In some variations the shape of the thermal transfer region (e.g., pad)is custom-shaped to minimize overlap with the hairline of the individualwearing the pad, so as to minimize disruption of hair styles/patternsacross a night of sleep. In this arrangement, the shape would maximizethe available skin area that is not covered by hair for minimizinginteractions with hair styles.

The thermal transfer region may be temperature-regulated by anyappropriate mechanism, including air- or water-cooling, as well assolid-state cooling (e.g., Peltier devices), or some combination ofthese. In variations in which the thermal transfer region is liquid(e.g., water or other liquid coolant) cooled, the system may include areservoir of cooling fluid that may be located separately from the restof the device. For example, a mask or thermal applicator (including athermal transfer region for contacting the patient's skin over theprefrontal cortex region) may be connected by tubing to the reservoir ofcooled fluid. The cooled fluid may be pumped through the thermaltransfer region to cool the skin and therefore apply hypothermic therapyto the prefrontal cortex. In general, any appropriate method of coolingthe thermal transfer region may be used, including non-fluid ornon-thermoelectric methods. For example, the thermal transfer region maybe cooled by gas, or phase change of liquid/gas, or other chemicalendothermic reaction.

In variations including tubing, the tubing may be positioned for optimalcomfort during sleep. For example, in some variations, tubes that directthermal transfer fluids to the mask may be configured to connect awayfrom the patient so that they do not interfere with patient's sleep orrisk entanglement with the patient's head or neck as the patient issleeping with a device on their head. In some variations, the thermaltransfer region is connected to the cooled fluid source by inlet/outlettubing coming out middle of forehead region of the mark or applicator.Individuals tend to sleep on their sides or backs such that the sides ofthe head and the back of the head can come in contact with the sleepingsurface or pillow.

Alternatively, in some variations any inlet/outlet tubing extends fromthe top of the mask, which may be useful when individuals sleep withtheir face down. The tubing may be made to swivel, bend, rotate, or flexrelative to the mask. For example, a junction between the applicator andthe tubing may be a rotating and/or swiveling junction, and may beflexible (particularly compared to more rigid applicator and tubingregions surrounding it).

The thermal transfer region may be connected and held to the patient'shead in any appropriate manner. Similarly, any tubing extending from theapplicator may be strapped or held so that it extends over top of headand exits middle of head. Another arrangement for connectors and tubingmay be over the forehead and out the top of the head, since this part ofthe head generally does not come in contact with the sleeping surface orpillow. In an alternate configuration, the inlet/outlet tubing comingout over the sides over temples is shaped or configured to course aroundears to back of head. Thus in one arrangement, tubing and connectorscourse over the temples and around the ears to the back of the head. Inthis arrangement, any tubing and connectors may be made relatively flatto minimize discomfort when the head is lying on them during sleep. Thetubing may also be configured so as not to leak or collapse, limitingthe heat transfer. Finally, the tubing may be insulated.

The systems described herein may be configured to be worn by the subjectevery night, and thus may include a washable, disposable, or replaceableskin-contacting region. In some variations the entire applicator isdisposable; in other variations only a portion is disposable. Forexample, the thermal transfer region may be covered by a disposablematerial or cover that can be replaced nightly with each use. Thedisposable region (e.g., cover) is generally adapted to transfer heatover all or a portion, so that the thermal transfer region mayeffectively apply hypothermic therapy to the skin over the frontalcortex. In some variation this cover is configured as a disposablebiogel cover.

In some variations the side tubing is integrated with one or more strapsfor holding the applicator that extend around the back of head. In anyof these variations, straps may be utilized to keep the mask on the headand include tubing and connectors integrated into the strap in order tominimize excess tubing/connectors/materials coming off of the mask.

In some variations the system includes a chin strap to help with keepingcap from rising off top of head. In this arrangement, a piece ofmaterial comes off the sides of the mask and wraps under the chin of thewearer. The purpose of this is to keep the mask from sliding off the topof the head as may occur during position changes across a night ofsleep. In some variations, strap tighteners on front of applicator maybe used for easy adjustment and minimal interference with back of headlying on pillow. Any appropriate material may be used for fastening orfasteners, such as Velcro, adhesives, snaps and other types offasteners, particularly those that minimize any bulk in areas of themask or straps that might produce discomfort. An example would be havingthe fasteners in the forehead region where they would not interfere withmask comfort when the head is lying on the sleeping surface.

In some variations the system may include one or more molds forapproximating forehead shape in general for similarly sized foreheadsand specific forehead moldings for individuals for their unique headsize. For example, the materials used for the mask may be specificallymolded for the general shape of a head and even more specifically may bemolded specifically for each individual who uses the mask to help withsleep. In general the thermal transfer region may have surface that isconfigured to maximize surface contact of the thermal transfer region tothe head surface (skin) to increase the efficiency of heat transfer tothe underlying cortex. This can be done by any permanent means such asproducing a fixed size mold using a nonmalleable material, or may bedone by any means in which some malleable material can be temporarilyshaped to the surface features after it has been placed on the head.Examples might include some form of expandable material with a gas orfluid filled cavity that can be inflated, or expanded to conform to theshape of the underlying head, foams, shape-memory materials, or thelike.

For example, in some variations the applicator includes one or moreinjection/vacuum chambers built into cap to increase comfort andincrease surface contact for maximizing thermal transfer. Injection orvacuum chambers may be integrated into the mask and can be inflated ordeflated to form the mask material to the shape of the head. Afterplacing the mask on the head, either removing liquids or gases fromchambers on the underside of the mask or injecting liquids or gases intosome outer layer may conform the mask to come in closer approximation tothe skin and given the natural curvature of the forehead may create anadhesive seal in which the mask may stay on the head. In one variationsthe applicator (e.g., mask) has a strapless design using only foreheadshape and using injection/vacuum chambers and/or adhesive materials tomaintain position of applicator. In this arrangement, some form oftemporary adhesion produced by either an adhesive material or somecombination of inflation/deflation, or temporary malleability of somematerial in the mask may serve the purpose of affixing the mask suchthat additional strappings or coverings to keep the mask in place arenot necessary. This strapless arrangement of the applicator may offerincreased comfort for some sleeping individuals so that no materialscome between the sides and backs of their heads as they lay down forsleep.

In some variations, an integrated eye pad may be included to block outlight and/or provide additional cooling of orbital frontal cortex toreduce metabolism in orbital frontal cortex before and during sleep.

In another arrangement, the mask may be constructed such that inaddition to covering a region of the head over the frontal cortex,additional materials extend down to cover the orbits over the eyes. Thismaterial could serve several functions. First, it may have thermaltransfer materials integrated into it so that the orbit is cooled withthe intent of cooling the underlying orbitofrontal cortex which mayfacilitate the metabolic reduction in frontal cortex areas that areconducive for sleep. Another function of this material is to blockvisual sensory stimuli that could interfere with sleep given the knowneffects of light on brain arousal. Another function of this material maybe to produce a relaxing, stress and anxiety reducing effect caused bythe sensation of cooling thermal transfer in this head area. This initself may facilitate sleep in addition to the effects on underlyingbrain metabolism. In some variations, the applicator may include thermalinsulation around the thermal transfer region to prevent cooling ofadjacent region (including the orbits of the eyes), which may beunnecessary and uncomfortable.

In some variations the device may include an integrated ear pad optionto either block out noise and/or supply audio input during sleep. Forexample, the applicator may be configured such that in addition tocovering a region of the head over the frontal cortex, additionalmaterials extend down to cover the ears. This material could serveseveral functions. First, it may have thermal transfer materialsintegrated into it so that the ear cavities, canals and sinuses arecooled with the intent of cooling the underlying temporal cortex whichmay facilitate the metabolic reduction in temporal cortex areas that areconducive for sleep. Alternatively or additionally, this material mayblock auditory sensory stimuli that could interfere with sleep given theknown effects of sound on brain arousal and/or may produce a relaxing,stress and anxiety reducing effect caused by the sensation of coolingthermal transfer in this head area. This may facilitate sleep inaddition to the effects on underlying brain metabolism.

In some variations the applicator may include (or be configured for usewith) an integrated neck pad to provide thermal stimuli to neck arteriesto cool the brain before and during sleep to reduce cerebral metabolismbefore and during sleep and thereby improve sleep quality. Severalarteries course through the neck in close approximation to the surfaceof the neck skin. In another arrangement, the mask would be constructedsuch that in addition to covering a region of the head over the frontalcortex, additional materials extend down to cover the neck. Thismaterial could serve several functions. First, it may have thermaltransfer materials integrated into it so that the neck is cooled withthe intent of cooling the underlying arteries that supply blood to thebrain as a whole which may facilitate a reduction in whole brainmetabolism that are conducive for sleep. Another function of thismaterial may be to produce a relaxing, stress and anxiety reducingeffect caused by the sensation of cooling thermal transfer in this headarea.

In another arrangement, the mask may be constructed such that inaddition to covering a region of the head over the frontal cortex,additional materials extend down to cover the sides and back of theneck. This additional material may have thermal transfer materialsintegrated into it so that the neck is cooled with the intent of coolingthe underlying brain regions such as the brainstem, cerebellum andoccipital cortex which may facilitate a reduction in metabolism to theseregions of the brain that may be conducive for sleep. This material mayalso produce a relaxing, stress and anxiety reducing effect caused bythe sensation of cooling thermal transfer in this head area. This initself may facilitate sleep in addition to the effects on underlyingbrain metabolism.

In some variations the system may be configured to provide coolingstimuli to nasal cavities/oropharynx before and during sleep for purposeof cooling/reducing metabolic activity in brainstem/hypothalamus tofacilitate sleep. For example, in another arrangement, methods toprovide thermal transfer in the area of the nasal cavities/oropharynx inthe back of the throat and nasal passages may be applied to cool theunderlying brain regions such as the upper brainstem, hypothalamus andorbitofrontal cortex which may facilitate a reduction in metabolism tothese regions of the brain that may be conducive for sleep.

In general, the devices and systems may be used combination with (andmay be integrated as part of) any other device intended to be worn by apatient during sleeping. For example, devices to treat respiration(e.g., respirators, ventilators, CPAP machines, etc.) may includeintegrated cooling systems such as those described herein to helpenhance sleep, and/or treat sleeping disorders.

As mentioned above, the system described herein may generally includeone or more sensors for monitoring either or both the patient and thesystem components (e.g., thermal transfer region). In some variationsthe system is configured to measure various parameters on theapplicator, including temperature sensors (to measure skin temperature)or electrodes (e.g., to measure EEG parameters) or the like. The systemmay be configured to provide feedback to the patient/clinician and/or toprovide feedback to the system (e.g., the controller) to modify activityof the system.

In addition, in some variations the systems and devices described hereinmay include additional therapeutic or non-therapeutic modalities whichmay enhance comfort, relaxation and/or sleep. For example, the systemsdescribed herein may include one or more vibratory actions or mechanismsto induce a vibratory/rhythmic/movement sensation on the skin. In onearrangement of the device, a physical sensation may be created thatcould facilitate sleep and/or produce a relaxing, anxiety or stressreduction purpose that could facilitate sleep and add to the othereffects of the device as otherwise noted. For example, physicalturbulence in the fluid channels may be permitted or generated. In thisarrangement of the device, the direction and movement of fluid withinthe channels of the thermal transfer pad are configured to have apleasing, relaxing, calming, stress reducing, massage like effect thatcould potentiate the positive sensations of the device for the wearer.Similarly, altering pumping pressures of the fluid in a rhythmic mannermay be optimized for comfort, soothingness, massaging feeling. In thisarrangement of the device, the direction and movement of fluid withinthe channels of the thermal transfer pad could be altered by variousconfigurations of alternating pressure cycles in the pump, therebycreating a more pleasing, relaxing, calming, stress reducing, massagelike effect that could potentiate the positive sensations of the devicefor the wearer.

In some variations, the system may incorporate a smell or odor stimulito help enhance comfort and/or effect. For example, the addition ofaromas may be subjectively consistent with relaxation/sleep. In thisarrangement of the device, the smell of the thermal transfer pad couldbe altered by various scents, thereby creating a more pleasing,relaxing, calming, stress reducing, effect that could potentiate thepositive sensations of the device for the wearer.

As mentioned above, the system may include either direct or indirectmodulation of sound when using the device. In general, soundssubjectively consistent with relaxation/sleep may be emitted by thesystems (either as part of the applicator or as part of the nearbydevice, even in variations not including earphones/headphones or thelike. In this arrangement of the device, sounds could be added to thethermal transfer pad or (for devices having a remote source of coolingfluid) to a remote unit connecting to the thermal transfer pad, therebycreating a more pleasing, relaxing, calming, stress reducing, effectthat could potentiate the positive sensations of the device for thewearer. As mentioned above, the device may include integrated ear padsor plugs with the thermal transfer pad to block out unwantedenvironmental noises that might interfere with sleep. In anothervariation of the device the system may be configured to emit whitenoise, or blocking noises, thereby cancelling out intermittent, variablenoises in the environment of the sleeping individual.

Controller

Any of the systems described herein may include a controller forregulating the temperature of the thermal transfer region and therebyproviding hypothermic therapy. In general, the controller (which may bereferred to as a hypothermic controller) may control both the appliedtemperature and the timing (or time-course) of the applied temperature.The controller may be typically configured to apply one or moretemperatures to the thermal transfer region for a predetermined amountof time, including following on or more time course for application ofcooling. The controller may include a plurality of inputs, includinguser-selectable inputs (controls for timing, on/off, etc.), as well asfeedback (e.g., from the skin surface, or other system feedbacks asdescribed below).

A dose or time course for activation may be referred to as a timeline,or algorithms, of thermal transfer on sleep. For example, in somevariations the system in configured to deliver a fixed time course. Inone arrangement, a constant thermal transfer rate can be maintainedwithout variation across the period of use. For example, the system maybe configured to deliver a dose prior to sleep only. In one arrangement,the thermal transfer applicator could apply treatment for 45 minutes to1 hour prior to getting in to bed to facilitate the sleep onset process.For example, the system may be configured to cool the thermal transferregion to approximately 14° C. to facilitating sleep onset; based onpatient comfort, this temperature may be adjusted to higher temperatures(e.g., up to 30° C.), or it may be a fixed temperature. Similarly, thesystem may be configured to ramp down to the final temperature (e.g., of10° C., 14° C., etc.) to allow a subject to acclimate to thetemperature). In this application, if effects on only sleep onset weredesired, the device could be removed at the time a person got into bed.

In some variations, the system may be configured or adapted for use onlywhen the patient has gone to bed, to operate even after the patient issleeping. In one arrangement, the applicator could be worn or appliedwhen a person got into bed, and hypothermic therapy applied over aportion or throughout a night of sleep to facilitate the sleep process(including across a night of sleep). In this arrangement, 14° C. orother low temperature (e.g., 10° C.) may be maximally effective, andhigher temperatures less effective, in facilitating deeper sleepespecially in the first half of the night, with less significant effectslater in the night.

In some variations the system may be configured to provide hypothermaltherapy both before desired sleep time (GNT) and after initially fallingasleep. For example, in one arrangement, the thermal transfer pad couldbe applied 45 minutes to 1 hour prior to getting in to bed to facilitatethe sleep onset process and left on throughout a night of sleep tofacilitate the sleep process across a night of sleep. Thus, thecontroller may be configured to initially apply a sleep onset timecourse (e.g., ramping to a sleep-onset temperature such as about 14° C.,and maintaining that temperature for a predetermined time period, suchas 30 min-1 hr), and then transition to a sleep maintenance time course(e.g., maintaining the temperature at a relatively low temperature suchas about 14° C. for the first 2-4 hours of sleep or for the rest of thenight, or gradually increasing the temperature to a higher levelthereafter). The maintenance time course may maintain deeper sleepacross the night with lesser degrees of facilitation in highertemperatures up to 30° C.

Thus, in some variations the time course is constant, while in othervariations, the time course is variable (including changes in thetemperature over the sleep period). For example, in one arrangement, avariable thermal transfer rate with defined changes can be deliveredacross the period of use. While changes in device temperature are feltimmediately at the skin surface, there is a delay between the time acooling stimulus is applied to the head surface and the time cooling isachieved in the underlying cortex. Variable time course algorithms,therefore, may include different delays built in between the time ofapplication and the time of the desired effect on either the temperaturesensation at the skin surface or on the temperature of the underlyingbrain and resulting effects on brain metabolism. In one arrangement adelay of approximately 30 minutes may be built in to the systemsvariable time course algorithms.

In some variations the systems described herein are configured for useprior to falling asleep (which may be referred to as pre-cooling devicesor systems). Thus, the device and method of operation may be configuredspecifically for being worn to increase drowsiness or decrease thelatency to sleep of a patient. The device may be adapted by includingtiming controls adapted for the pre-sleep cooling described herein. Insome variations the system may be configured to differentiate betweenlong and short sleep periods; for example, the system may be configuredto facilitate “napping” (short sleeps) or longer-duration sleeping. Insome variations the system includes controls (and timers) for selectingsleep duration, and may alter the applied hypothermic therapy on thebasis of the control. In the napping mode the system may provide aninitially high level of cooling (e.g., to between 10° C. and 18° C.) andshift after a first time period to a higher temperature (e.g., 24° C.,or some temperature between about 20-28° C.) or shift to a thermally“neutral” temperature (e.g., about 30° C.). In some variations, thesystem or device is configured as a “napping” device as opposed to a 6-8hour sleep period device.

As mentioned above, in some variations the system includes one or moreramping time courses. For example, the thermal transfer region could beapplied at a neutral temperature of approximately 30° C. at 45 minutesto 1 hour prior to getting in to bed, and then the temperature rampeddown to approximately 14° C. (e.g., between 10 and 25° C.) over a matterof minutes, while adjusting the rate of ramping to skin surface comfortlevels, to facilitate the sleep onset process. Similarly, any settemperature could be achieved by first applying the device at a neutralcomfortable skin temperature then ramping the temperature over time toachieve the desired final endpoint temperature.

In some variations the time course may be varied based on eitherpredetermined values or based on feedback. For example, a sleepmaintenance time course may be applied that may include varying the timecourse of thermal transfer in coordination with the probability of NREMand REM sleep stage occurrences. Brain temperature as well as brainblood flow and brain metabolism vary in characteristic ways across anight of sleep and is dependent on the stage of sleep an individual maybe in as well as the duration of time from the beginning of sleep. NREMsleep stages include lighter stage 1 sleep, deeper stage 2 sleep anddeepest stages slow wave sleep with slow wave sleep predominating in thefirst half of the night. REM sleep occurs cyclically across a night,every 60-90 minutes with progressively longer and more intense REMperiods occurring in the latter parts of the night. Brain temperature,blood flow and metabolism tend to lessen in deeper NREM sleep andincreases in REM sleep. The degree to which these changes occur arethought to be functionally important for sleep. The cooling device maytherefore facilitate the deepening of NREM sleep by applying a timecourse that mimics or follows the time course of a normal sleep cycle.This may result in reducing metabolic activity in the frontal cortexwith consequent increases in slow wave sleep.

In one arrangement of a variable thermal transfer time course,therefore, the maximal cooling may be concentrated earlier in the nightwhen slow wave sleep tends to be maximal, with less significant coolingtowards the end of the night when REM sleep and natural brain warmingwould be occurring. One algorithm (e.g., time course) may thereforeinclude a thermal transfer at the coolest temperature tolerated withoutdiscomfort (e.g., between about 10° C. and about 14° C. at the beginningof the night and ramping to a neutral 30° C. temperature by the end of anight's sleep). This ramping could be linear across the night, or couldhave a curvilinear component where maximal cooling is concentrated inperiods where slow wave sleep has a high probability of occurring asrevealed by normative curves of slow wave sleep production across thenight.

It is known that some disorders, such as depression for example, havecharacteristic alterations in REM sleep. The dose-ranging research studyabove demonstrates that altering the temperature of the thermal transfermask has predictable effects on the occurrence of REM sleep. Onealgorithm, therefore, may include a variable thermal transfer across thenight that is intended to target the occurrence of REM sleep in atherapeutic manner. In depression, for example, where REM sleep durationand intensity seem to be more highly concentrated in the first third ofthe night, use of a time course having a temperature of the coolesttolerable temperature (e.g., 14° C.) over this period would be expectedto inhibit abnormal REM sleep production whereas the use of more neutraltemperatures in the latter half of the night would be expected to leadto more normal REM sleep production in that part of the night.

Similarly, alterations in REM and NREM sleep can occur in a variety ofneuropsychiatric disorders. The general principle of altering thetemperature of the thermal transfer region of the applicator tofacilitate or diminish discrete aspects of deep NREM sleep or REM sleepthat are directly related to the specific disorder would be expected tohave therapeutic utility specific to the disorder.

As mentioned briefly above, the system may include feedback to thecontroller to regulate the applied hypothermic therapy. Surprisingly,altering the applied hypothermic therapy has a predictable effect onsleep physiology, as described above. It may be possible, therefore, tomeasure the changes in sleep physiology and incorporate them into afeedback loop that then results in changes in the thermal transfer. Inthis manner, the amount of thermal transfer applied can be adjusted inreal time to achieve some desired physiological effect.

In one arrangement a variable thermal transfer rate with defined changescan be delivered across the period of use with the changes linked tofeedback from changes in the physiology of the body across a period ofuse. Physiological measures may be monitored and thermal transferadjusted in real time according to the level of the physiologicalmeasure. For example, the system may include feedback based on thepresence or absence of REM or NREM sleep as assessed by any method ofREM/NREM sleep assessment, such as EEG frequency, Heart RateVariability, Muscle Tone or other mechanism. Thus, the device or systemmay include one or more sensors (electrodes, etc.) that provide at leastsome indication of sleep cycle, this information may be fed or monitoredby the controller, which may modulate the applied dose based on thedetected REM/NREM status. The perceived status may be compared to anexpected or desired status, which may alter the applied hypothermictherapy.

In some variations, the system may also or alternatively monitor and/orreact to the depth of slow wave sleep, as measured by EEG wave analysisor other mechanism. Similarly, the system may monitor and/or respond tothe degree of autonomic arousal as measured by HR variability or othermechanism. Other examples of characteristic that may be (separately orin combination) monitored and/or feed back into the system to modulatethe applied hypothermy is galvanic skin response, skin temperature, eyemotion during sleeping, and gross body motion during sleeping. Forexample, skin temperature may be measured either at the skin on the headunderneath the device, or on skin at some other portion of the head notunderneath the device, or peripheral skin temperature, or core bodytemperature (measured internally or by some external means) or somecombined measure assessing thermoregulation of the head and periphery,or core body to peripheral temperature measure. Eye motion or bodymotion may be monitored optically or through one or more motion orposition sensors (including acceleratomers).

In many of the systems and devices described herein the control may beadjusted by the subject wearing the device (and/or by a physician orother professional). In some variations, the person wearing the devicecan modify the thermal transfer rate across the period of use with thechanges linked to subjective feedback. For example, a control on thedevice may allow the person wearing the device to adjust the temperatureaccording to their immediate comfort and treatment needs, either up ordown some small increments.

In another arrangement, an individual can set their go to bed times anddesired get out of bed times, then a preprogrammed algorithm is input tostart and stop at those times and provide the incremental adjustments tooccur on a relative basis over this time period. These automated timecalculations could be implemented for any variable schedule of thermaltransfer rates across any defined period of time.

In general, the temperature of the skin beneath the applicator (e.g.,the thermal transfer region of the applicator) may also be monitored.Although the system and/or device may apply a predetermined temperatureto the skin through the applicator, the temperature of the skin does notnecessarily become cooled to this temperature, but is typically higher.In some variations skin temperature beneath the thermal transfer regionmay be monitored and/or fed back into the controller to regulate theapplied temperature. As mentioned above, the thermal contact between theskin and the applicator may be optimized or regulated. For example, thematerials forming the applicator (and particularly the thermal transferregion) may be optimized or otherwise selected to determine thetemperature applied. In one variation the lining of the transfer padthat comes in contact with the skin is a hydrogel allowing for increasedsurface area contact and increased thermal transfer characteristics. Inanother arrangement, this lining is combined with dermatologic productsthat can be rejuvenating for the skin when in contact over the course ofa night. In another arrangement, an inner lining can be refreshed on anightly or less frequent basis that can benefit the skin when appliedover the night of sleep.

During the daytime, when not in use, the cooling chamber, any tubing andheadgear may be stored until the next night's use. In some variationsthe device is self-contained (e.g., battery powered, particularly forsolid-state devices). Thus the device may be re-charged when not in use.In one arrangement, the equipment can all be contained in a storage boxfor an attractive appearance, which may also be functional (e.g.,recharging, sanitizing, protection, etc.). In variations includingtubing, the tubing can automatically recoil into a storage region (e.g.,box) when not in use for maintaining an attractive appearance. In somevariations, the applicator is stored with antiseptic materials and/or inan environment that provide for antiseptic cleaning and storage tominimize the potential for growth of organisms that may be harmful tothe wearer.

Because the device is intended for use at night, the controls may beoptimized for use in low lighting. A subject using the device may haveto interact with the device at night when illumination would be expectedto be low, thus in some variations, the device or system includescontrol features that the individual needs to interact with would becomelit only when an individual comes in close contact with the device.

In another arrangement of the device, control features may be made of anillumination level that minimally interferes with sleep. In anotherarrangement of the device, control features may be voice activated. Inanother arrangement of the device, control features have physicalfeatures that can be identified by touch and differentiate themselvesfrom other parts of the device to let an individual know in the darkwhere the control buttons are located.

In general, it may be particularly desirable to include one or morefeatures that record (and/or analyze) use of the device or system. Forexample, in the clinical management of a patient, a healthcare providermay want to know certain parameters of the patient and/or device overmultiple nights of use such that care can be optimized. In somevariations, the system or device includes memory (e.g., a memory card ormemory chip) that may automatically record certain parameters and storethem for later display by the healthcare provider. For example, theoperation of the controller may be recorded.

In monitoring their own care, a device user may want to know certainparameters of the patient and/or device over multiple nights of use suchthat care can be optimized. In one arrangement of the device, therefore,memory may automatically record certain parameters and store them forlater display. This information could be transferred to a healthcareprovider's office or some other central database via the phone orinternet or some wireless technology where someone could review theinformation and provide recommended adjustments in the treatmentaccordingly. Examples of information that may be stored could include,but would not be limited to: temperature of the device; skintemperature; core body temperature; measures of autonomic variability;depth of sleep as assessed by NREM sleep, EEG power in discretefrequency bands, REM sleep or other sleep staging; periods of activityand/or wakefulness across the night; subjective measures of sleepdepth/comfort/satisfaction; and sleep duration.

In some variations this information may be automatically collected,while in other variations it may be entered by the subject or a thirdparty.

Indications and Methods for Operation

As mentioned above, the systems and devices described herein maygenerally be used to treat sleeping disorders. In particular, thesesystems and methods may be used to treat insomnia. Thus, the systems anddevices described herein may be used to facilitate sleep. For example,the systems and devices described herein may be used to decrease sleeplatency (e.g., the time to fall asleep), and/or increase sleep duration.

In operation, a method of modulating sleep (e.g., increasing sleepduration) may include the steps of positioning and/or securing thethermal transfer region on the forehead or scalp of the subject (who mayalso be referred to as a patient) in the region over the area of thefrontal cortex and (in some variations) related areas. The system ordevice may then apply hypothermic therapy (e.g., cooling) to the skin toreduce metabolic activity in the underlying frontal cortex and relatedareas thereby facilitating or modulating sleep.

As discussed above, in some variations the systems and device may beapplied prior to sleep to aid in sleep onset. For example, the systemmay include the step of applying the thermal transfer region in contactwith the skin over the prefrontal region for a time period (e.g., 15minutes, 30 minutes, 45 minutes, 60 minutes, etc.) before a desired goodnight time (GNT, the desired time to fall asleep). Regional hypothermiamay be used alone or in conjunction with other relaxation and/orpre-sleep therapies to enhance sleepiness and decrease the latency tosleep.

In some variations, the method of use may include (or be limited to) amethod of increasing slow wave sleep, a method of increasing sleepmaintenance, a method of reducing awakenings, and/or a method ofincreasing the time spent asleep across the night. In general, each ofthese methods may include the steps of placing the applicator (includingthe thermal transfer region) in contact to transfer thermal energy fromthe subject's skin above the prefrontal cortex. Thereafter, the systemmay execute a treatment regime including cooling to a temperature suchas the lowest temperature that may be tolerated by the subject withoutresulting in discomfort (including arousals) such as pain or tissuedamage. Typically this temperature may be between about 10° C. and about25° C. (e.g., 11° C., 12° C., 13° C., 14° C., 15° C., 16° C., etc.). Thetemperature may be lowered slowly (e.g., in a ramp, such a linear ramp)or more quickly. The treatment regime may hold this first targettemperature for a first time period (which in some cases may be apredetermined time period such as 1 hour, 2 hours, 3 hours, 4 hours, 5hours, etc.) or it may be determined based on patient feedback and/orcontrol setting. Thereafter the temperature may be increased and/ordecreased in one or a series of dosage settings. In some variations thedosage follows a predetermined treatment parameter that increases thetemperature from an initially low value to a slightly higher temperaturelater in the evening to help maintain sleep.

Any of the methods described herein may be used to treat insomniacs,however these methods may also be used to generally improve healthysleep, even in non-insomniac subjects. In particular, these methods,devices and systems may be used to improve sleep in individuals whoexperience sleeplessness.

Further, the systems and devices described herein may be used as part ofa method to treat and improve sleep in individuals with neuropsychiatricdisorders such as, but not limited to, depression, mood disorders,anxiety disorders, substance abuse, post-traumatic stress disorder,psychotic disorders, manic-depressive illness and personality disordersand any neuropsychiatric patient who experiences sleeplessness.

Sleep reduction and disruption is known to be associated as aco-morbidity in a number of disorders, and the devices and systemsdescribed herein may be used to help alleviate such disorders, in partby helping modulate and enhance sleep. For example, the devices andsystems described herein may be used to improve sleep in patients withpain, including chronic pain, and headaches, including migraineheadaches, and cardiac, endocrinologic, and pulmonary disorders, andtinnitus.

The systems and devices may also be used in a waking subject to enhancerelaxation and improve waking function. The treatment regime may besimilar or different from the treatment regimes used to enhancesleepiness and/or prolong sleep. For example, the devices and systemsdescribed herein may be used to improve waking function by reducingmetabolic activity in the frontal cortex during waking, including:reducing the experience and distress of tinnitus and chronic pain;increasing mental and cognitive focus; producing a subjective feeling ofrelaxation; producing a subjective feeling of soothing; producing asubjective feeling of comfort; producing a subjective feeling of stressreduction; improving mood in patients with depression; reducing fears,anxieties in patients with anxiety disorders; reducing distractingthoughts; and/or reducing obsessive thoughts, and behaviors.

In such non-sleeping variations, it may be useful to allowsubject-control of the system, including subject control of the durationand level of cooling applied. In some variations pre-determined settingsfor different applications may be included as part of the system.

Another application of the systems and devices described herein includesthermoregulation and fever reduction. The devices and systems may beused to reduce generalized fever and could be utilized for fevercontrol, particularly in individuals with elevated core bodytemperatures from a variety of causes, including, but not limited to,infection. In some variations the systems and devices described hereinmay be used or configured for use in conjunction with (or integratedinto) a system for light therapy for Circadian Rhythm Disorders (“CRD”).

In addition, the devices and systems described herein may also be usedto alter circadian rhythms and could therefore be applicable for use incircadian rhythm disorders such as shift work disorder, phase advanceand phase delay circadian rhythm disorders.

Although the foregoing invention has been described in some detail byway of illustration and example for purposes of clarity ofunderstanding, it is readily apparent to those of ordinary skill in theart in light of the teachings of this invention that certain changes andmodifications may be made thereto without departing from the spirit orscope of the appended claims.

What is claimed is:
 1. A method of reducing sleep onset bynon-invasively applying hypothermal therapy to a subject's frontalcortex, the method comprising: positioning an applicator comprising athermal transfer region in communication with the subject's skin overthe subject's prefrontal cortex; passing cooled fluid through theapplicator so that the thermal transfer region is cooled to a firsttemperature between about 10° C. and about 25° C.; maintaining the firsttemperature for a first time period extending at least 15 minutes. 2.The method of claim 1, further comprising maintaining contact betweenthe subject's skin over the subject's prefrontal cortex and the thermaltransfer region so that the metabolism in the prefrontal cortex isslowed.
 3. The method of claim 1, wherein positioning the applicatorcomprises securing the applicator in position.
 4. The method of claim 1,wherein positioning the applicator comprises adhesively securing theapplicator.
 5. The method of claim 1, wherein positioning the applicatorcomprises securing the applicator over just the subject's foreheadregion.
 6. The method of claim 1, wherein passing a cooled fluid throughthe applicator comprises ramping the temperature of the thermal transferregion from ambient temperature to the first temperature over at leastfive minutes.
 7. The method of claim 1, further comprising warming thethermal transfer region to a neutral temperature at the end of a night'ssleep.
 8. The method of claim 1, wherein maintaining the firsttemperature comprises maintaining the first temperature for at least 30minutes.
 9. The method of claim 1, wherein maintaining the firsttemperature comprises maintaining the first temperature for at least onehour.
 10. The method of claim 1, further comprising changing thetemperature of the thermal transfer region to a second temperature. 11.The method of claim 1, further comprising passing cooled fluid throughthe applicator so that the thermal transfer region is cooled to a secondtemperature that is between the first temperature and 30° C.
 12. Themethod of claim 11, wherein the second temperature is between about 20°C. and about 25° C.
 13. The method of claim 11, further comprisingmaintaining the second temperature for a second time.
 14. The method ofclaim 11, further comprising maintaining the second temperature for morethan one hour.
 15. The method of claim 11, further comprisingmaintaining the second temperature for more than four hours.
 16. Themethod of claim 11, further wherein the second temperature is maintainedby adjusting the fluid temperature based on sleep-cycle.
 17. The methodof claim 11, further wherein the second temperature is maintained byadjusting the fluid temperature based on subject selection of auser-selectable input.
 18. The method of claim 1, wherein the method ofreducing sleep onset is a method of reducing sleep onset in a subjectwith insomnia.
 19. A method of reducing sleep onset by non-invasivelyapplying hypothermal therapy to a subject's frontal cortex, the methodcomprising: positioning an applicator comprising a thermal transferregion in communication with the subject's skin over the subject'sprefrontal cortex; cooling the thermal transfer region to a temperaturebetween about 10° C. and about 25° C.; and maintaining contact betweenthe subject's skin over the subject's prefrontal cortex and the thermaltransfer region so that the metabolism in the prefrontal cortex isslowed.
 20. The method of claim 19, further comprising maintaining thecontact between the subject's skin over the subject's prefrontal cortexand the thermal transfer region for at least 15 minutes.
 21. The methodof claim 19, further comprising maintaining the contact between thesubject's skin over the subject's prefrontal cortex and the thermaltransfer region for at least 30 minutes.
 22. The method of claim 19,further comprising warming the then al transfer region to a neutraltemperature at the end of a night's sleep.
 23. A method of reducingsleep onset by non-invasively applying hypothermal therapy to asubject's frontal cortex, the method comprising: positioning anapplicator comprising a thermal transfer region in communication withthe subject's skin over the subject's prefrontal cortex; passing cooledfluid through the applicator so that the thermal transfer region iscooled to a first temperature between about 10° C. and about 25° C.; andmaintaining the first temperature and the contact between the subject'sskin over the subject's prefrontal cortex and the thermal transferregion so that the metabolism in the prefrontal cortex is slowed. 24.The method of claim 23, further comprising passing cooled fluid throughthe applicator so that the thermal transfer region is cooled to a secondtemperature that is between the first temperature and 30° C.
 25. Amethod of sustaining sleep in a subject by non-invasively applyinghypothermal therapy to the subject's frontal cortex, the methodcomprising: positioning an applicator comprising a thermal transferregion in communication with the subject's skin over the subject'sprefrontal cortex; maintaining, after the subject has fallen asleep, thethermal transfer region at a temperature at or between the lowesttemperature that may be tolerated by the subject without resulting indiscomfort or arousal from sleep and 25° C.; and maintaining thetemperature for a first time period extending at least 30 minutes. 26.The method of claim 25, wherein the temperature is between about 10° C.and about 18° C.
 27. The method of claim 25, wherein positioning theapplicator comprises adhesively securing the applicator.
 28. The methodof claim 25, wherein positioning the applicator comprises securing theapplicator over just the subject's forehead region.
 29. The method ofclaim 25, wherein the method of sustaining sleep in a subject is amethod of sustaining sleep in a subject with insomnia.
 30. The method ofclaim 25, further comprising warming the thermal transfer region to aneutral temperature at the end of a night's sleep.
 31. A method ofsustaining sleep in a subject by non-invasively applying hypothermaltherapy to the subject's frontal cortex, the method comprising:positioning an applicator comprising a thermal transfer region incommunication with the subject's skin over the subject's prefrontalcortex; maintaining, after the subject has fallen asleep, the thermaltransfer region at a temperature between about 10° C. and about 25° C.;and maintaining the temperature for a first time period extending atleast 30 minutes.
 32. The method of claim 31, wherein the temperature isbetween about 10° C. and about 18° C.
 33. The method of claim 31,wherein maintaining the temperature for the first time period comprisespassing cooled fluid through the applicator so that the thermal transferregion is cooled to a temperature between about 10° C. and about 25° C.34. The method of claim 31, wherein positioning the applicator comprisesadhesively securing the applicator.
 35. The method of claim 31, whereinpositioning the applicator comprises securing the applicator over justthe subject's forehead region.
 36. The method of claim 31, wherein themethod of sustaining sleep in a subject is a method of sustaining sleepin a subject with insomnia.
 37. The method of claim 31, furthercomprising warming the thermal transfer region to a neutral temperatureat the end of a night's sleep.
 38. A method of sustaining sleep in asubject by non-invasively applying hypothermal therapy to the subject'sfrontal cortex, the method comprising: positioning an applicatorcomprising a thermal transfer region in communication with the subject'sskin over the subject's prefrontal cortex; maintaining, after thesubject has fallen asleep, the thermal transfer region at a temperatureat or between the lowest temperature that may be tolerated by thesubject without resulting in discomfort or arousal from sleep and 25°C.; and maintaining the temperature while maintaining contact betweenthe subject's skin over the subject's prefrontal cortex and the thermaltransfer region so that the metabolism in the prefrontal cortex isslowed.